Researchers at the Centers for Disease Control and Prevention (CDC) estimated that as many as 47 million Americans may exhibit a cluster of medical conditions (“metabolic syndrome”) characterized by abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose. Having three or more traits of metabolic syndrome significantly increases the risk of dying from coronary heart disease or cardiovascular disease. It has also been reported that patients with even one or two metabolic syndrome traits, or those with metabolic syndrome but without diabetes also were at increased risk for death from coronary heart disease or cardiovascular disease.
Obesity and atherosclerosis have a major impact on morbidity and mortality in the United States and many other countries. Elevated cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is a major risk factor for atherosclerosis. Thyroid hormone replacement in hypothyroid individuals reduces total cholesterol and LDL-cholesterol. An excess of thyroid hormone in thyrotoxicosis causes weight loss. The weight loss consists not only of fat but also muscle mass and even myopathy can be observed.
The ability of thyroid hormone to lower cholesterol when given to hypothyroid individuals prompted efforts to design analogs that take advantage of these properties in the treatment of hypercholesterolemia. This action is the result of an accelerated LDL-cholesterol clearance rate. Triiodothyronine increases levels of both the hepatic LDL receptor and its mRNA. Additional thyroid hormone actions on lipid metabolism include increasing the activity of lipoprotein lipase.
Numerous studies have been carried out to synthesize thyroid hormone analogs that mimic the actions of the natural hormones. The objective of most of these efforts has been to develop thyromimetics that lower plasma cholesterol without adverse cardiac effects. A series of thyroxine analogs and methods of synthesis are described in U.S. Pat. No. 3,109,023. Thyroid hormone agonists that are highly selective for the thyroid hormone receptor (TR) β-subtype are described in U.S. Pat. No. 5,883,294 and WO 00/39077. U.S. Pat. No. 5,284,971 describes a class of thyromimetics, which have the distinguishing characteristic of a sulfonyl bridge in the diphenyl core. U.S. Pat. No. 6,534,676 describes a thyroid hormone analog 3,5-diiodothyropropionic acid (“DITPA”) for treating patients with congestive heart failure.
The usual method employed in treating obesity has been reduction of caloric intake either by reduced caloric diet or appetite suppression. An alternative method is to stimulate metabolic rate in adipose tissue. Adipose tissue is the largest storehouse of energy in the body (in the form of triglycerides) and typically makes up 15-20% or more of the body weight in men and 20-25% more of the body weight in women. U.S. Pat. Nos. 4,451,465, 4,772,631, 4,977,148 and 4,999,377 disclose compounds possessing thermogenic properties at dosages causing few or no deleterious side-effects, such as cardiac stimulation. Goglia and Lanni in WO2005009433 describe the use of a breakdown product of thyroid hormone (3,5-diiodothyronine) as a regulator of lipid metabolism to stimulate burning of fatty acid in mitochondria.
There is a need in the art for improved methods and compositions for stimulating weight loss and lowering triglyceride levels in overweight individuals, including those with metabolic syndrome.